Cerebrovascular disorders are diseases causing an enormous loss in healthcare economy, as they are the second and third most common causes of death in Japan, U.S.A. and Europe as well as the first leading cause of severe sequalae. At present, although active causal treatment is implemented for some patients of cerebral embolism and cerebral thrombosis (e.g., tPA, etc.), the portion of the subject under the benefit is limited to a few percents of the total patients' group, owing to the restriction in therapeutic time window. In most cases, patients are provided only with maintenance therapy for the purpose of preventing cerebral edema and suppressing recurrence and augmentation of the disorder (e.g., antithrombolytic drug), and an effective medicine targeting radical treatment and cerebroprotection is still not available.
It is well recognized that cells of the central nervous system are vulnerable to ischemic stress, and according to basic experiments using a cerebral ischemic model, it is reported that an ischemic state maintained for only a few minutes can cause irreversible impairment and finally death of neuronal cells. It is undeniable that such results have brought about great despair in the clinical field of cerebral stroke. However, in recent years, active research in the realm of neural science has revealed various potential aspects in solving problems such as response to various stresses at the level of individual cells upon ischemic loading, crosstalk between neuronal cells and glial cells, and programmed cell death, and these aspects are highly expected to be linked to the keys to proactive therapeutic strategy. However, although a number of products under development which have various action mechanisms, for example, glutamate antagonist, calcium antagonist, antioxidant and the like have been on trial heretofore, they all failed in the clinical tests. In Japan, Radicut (registered trademark, Mitsubishi Welpharma Kabushiki Kaisha), which is an antioxidant agent, has been approved, but this agent is not yet approved in abroad countries, and a cerebroprotective agent that has been approved worldwide is not available yet.
In association with an improvement in the intensive care system for patients having stroke, brain hypothermia treatment is available as a cerebroprotective therapy, effectiveness of which has been clinically reexamined. The brain hypothermia treatment is based on lowering of the brain temperature (cerebral temperature) to 32 to 35° C. and maintaining at that temperature, and is increasingly getting attention for its remarkable cerebroprotective effect. However, this treatment requires intensive treatment facilities and 24-hour intensive care by a plurality of medical staffs, such that propagation of the treatment as a general therapeutic method is still difficult.
In addition, one of 5 Japanese has some kind of problem with sleep, and users of hypnotics are increasing year by year. Sleep disorders are classified broadly into 4 categories of difficulty in falling asleep and maintaining sleep (insomnia), sleep excess disorder, sleep-wake rhythm disorder, and functional disorder associated with sleep stage or partial awakening (abnormal behavior during sleep). As remedies for insomnia, benzodiazepine receptor agonist is mainly used. However, benzodiazepine receptor agonist has side effects such as motor dysfunction, memory disorder and dependency, thus the development of hypnotics without these side effects has been expected.
Meanwhile, cannabinoid receptors have been identified since 1990's as receptors for Δ9-tetrahydrocannabinol (Δ9-THC), which is an active substance obtained from the hemp plant. At present, the CB1 receptor (see Nature, Vol. 346, p. 561 (1990)), its splice variant CB1a (see J. Biol. Chem., Vol. 270, p. 3726 (1995)), and the CB2 receptor (see Eur. J. Biochem., Vol. 232, p. 54 (1995)) are known. Almost around the same time, N-arachidonoylethanolamine (anandamide), an endogenous ligand for the CB1 receptor, was discovered from the brain of a pig (see Science, Vol. 258, p. 1946 (1992)). Anandamide belongs to the family of N-acylated ethanolamine, as does N-palmitoylethanolamine or N-oleoylethanolamine. Fatty acid amides including these N-acylated ethanolamines are found to have effect on physiological functions such as pain (see Nature, Vol. 394, p. 277 (1998); and Pain, Vol. 76, p. 189 (1998)), dietary regulation (see Nature, Vol. 414, p. 209 (2001)) and promotion of sleep (see Science, Vol. 268, p. 1506 (1995)). The route for biosynthesis or decomposition of fatty acid amides has been investigated since 1980's. First, a calcium-dependent transacylase produces anandamide, which is N-acylphosphatidylethanolamine (see J. Neurochem., Vol. 41, p. 1303 (1983)), and then a fatty acid amide is released therefrom by the action of phospholipase D (see J. Neurochem., Vol. 42, p. 1613 (1984)). The existence of an enzymatic activity which hydrolyzes a fatty acid amide into the corresponding fatty acid, thereby eliminating its physiological activity, was suggested earlier but was confirmed only in the later half of 1990's. An active substance hydrolyzing oleamide was isolated from a rat, and its cDNA was cloned (see Nature, Vol. 384, p. 83 (1996)). The enzyme produced by genetic recombination of the cDNA was able to hydrolyze various fatty acid amides including oleamide and anandamide, and was named as fatty acid amide hydrolase (hereinafter, sometimes abbreviated to “FAAH” in the present specification). Still, it is not sufficiently clear about the enzyme responsible for biosynthesis of fatty acid amides. However, the fact that fatty acid amides are produced from neuronal cells in a calcium-dependent, that is, neuronal activity-dependent manner (see Nature, Vol. 372, p. 686 (1994)), is highly meaningful for development of a therapeutic agent. Furthermore, a FAAH knockout mouse has been produced, and a FAAH inhibitory agent has been discovered, so that the physiological significance of FAAH inhibition is being revealed. In the FAAH knockout mouse, the content of fatty acid amides, including anandamide, in the brain increased by 10 to 15 times, but the mobility, body weight and body temperature of the mouse were normal. However, a decrease in the responsiveness to pain was observed, and this was interrelated to the content of fatty acid amides in the brain (see Proc. Natl. Acad. Sci. USA, Vol. 98, p. 9371 (2001)). For the FAAH inhibitor, trifluoromethyl ketone derivatives (see J. Am. Chem. Soc., 118, 5938 (1996)), alpha-keto heterocyclic ring derivatives (see Proc. Natl. Acad. Sci. USA, Vol. 97, p. 5044 (2000)), sulfonylfluoride derivatives (see Biochem. Biophys. Res. Commun., Vol. 231, p. 217 (1997)), fluorophosphonate derivatives (see Biochem. Pharmacol., Vol. 53, p. 255 (1997)), and arylcarbamate derivatives (see Nat. Med., Vol. 9, p. 76 (2003)) are known.
In addition to this, FAAH or anandamide is reported to be involved with various diseases, and it has been reported that large quantities of FAAH are found in the brain of Alzheimer's patients (see The Journal of Neuroscience, Vol. 23, p. 1136 (2003)). It has been also discovered by a test using rats that an increase in the amount of anandamide results in an antiparkinsonian activity (see Neuropsychopharmacology, Vol. 29, p. 1134 (2004)). It has been also reported that women having miscarriage show decreased levels of FAAH (see J. Clin. Endocrinol. Metab., 89, 5168 (2004)). Anandamide is reported to inhibit propagation of rectal cancer (see Gastroenterology, Vol. 125, p. 677 (2003)). It is reported that an FAAH knockout mouse is not susceptible to colonitis or colitis (see J. Clin. Invest., Vol. 113, p. 1202 (2004)). A FAAH inhibiting drug is reported to exhibit an anxiolytic activity (see Nature Medicine, Vol. 9, p. 76 (2003)). FAAH is reported to be an enzyme hydrolyzing oleylethanolamide, which is a satiety factor present in the small intestine (see Nature, Vol. 414, p. 209 (2001)). FAAH is a hydrolytic enzyme for stearoylethanolamide, and it is reported that administration of stearoylethanolamide to a mouse suppresses eating (see FASEB Journal, Vol. 18, p. 1580 (2004)). Since anandamide is an agonist of the vanilloid receptor, which is a nociceptor, the FAAH inhibitory agent is expected to have the same activity as that of the vanilloid receptor agonist (for example, prophylactic and/or therapeutic activity for frequent urination, urinary incontinence, interstitial cystitis) (see JP 2002-202204 A).
As such, FAAH is reported to be involved with various diseases, but there has been no report to the present, demonstrating the cerebro-neuroprotective effect of FAAH.
Since FAAH is an enzyme which hydrolyzes an endogenous sleep substance: oleamide, a FAAH inhibitory agent suppresses the decomposition of oleamide to induce sleep (US 2003/0092734 A).
In addition, as a compound represented by the formula (I):
wherein Z represents an oxygen or a sulfur,R1 represents an optionally substituted aryl, or an optionally substituted heterocyclic group, R1a represents a hydrogen atom, an optionally substituted hydrocarbon group, hydroxy, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted amino, or a 5- to 7-membered saturated cycloamino which may be substituted,R2 represents an optionally substituted piperidin-1,4-diyl or an optionally substituted piperazin-1,4-diyl,R3 represents a divalent group formed by removing two hydrogen atoms from an optionally substituted 6-membered ring, andR4 represents a group formed by removing one hydrogen atom from an optionally substituted benzene ring or an optionally substituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom, for example,(a) WO 2004/099164 discloses 2,2-dichloro-N-[3-[3-[2-chloro-6-(4-phenylcarbamoylpiperazino)phenyl]-5-isoxazolyl]phenyl]acetamide,(b) Bioorganic & Medicinal Chemistry Letters (2004), 14(22), 5513-5519 discloses a compound wherein R3 is pyridazin-3,6-diyl,(c) WO 2003/045313 discloses a compound wherein R1 is an optionally substituted quinolyl,(d) WO 2002/083134 discloses a compound wherein R2 is piperidin-1,4-diyl substituted with cyclopropylmethylaminomethyl,(e) U.S. Pat. No. 6,432,947 and WO 9837079 disclose a compound wherein R2 is piperazin-1,4-diyl substituted with an optionally substituted carbamoyl or an optionally substituted carbamoylmethyl, respectively,(f) WO 2002/005819 discloses 4-biphenyl-4-yl-N-{3-[2-(diisopropylamino)ethoxy]-4-methoxyphenyl}-3-methylcyclohexanecarboxamide,(g) WO 2001/066551 discloses a compound wherein R4 is a group formed by removing one hydrogen atom from a 5- to 6-membered heterocyclic ring substituted with 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl and 1-(4-chlorobenzoyl)propyl,(h) WO 2000/052001 discloses 4-biphenyl-2-yl-N-(3-methoxy-5,8-dihydroquinoxaline-2-yl)piperazine-1-carboxamide,(i) WO 98/00402 discloses 4-(4-methoxybiphenyl-3-yl)-N-(2-methoxy-4,5-dimethylphenyl)piperazine-1-carboxamide,(j) WO 96/21648 discloses a compound wherein R1 is 5-ethyl-2-methoxy-6-methyl-3-pyridinyl,(k) WO 96/01820 discloses a compound wherein the group formed by removing one hydrogen atom from an optionally substituted benzene ring or an optionally substituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom, represented by R4, is 1-(4-chlorobenzoyl)propyl-1,5-dihydro-5-oxo, and(l) JP-A 62-89679 discloses 1-[4-(4,5-dihydrofuran-2-yl)phenyl]-N-pyridin-4-ylpiperidine-4-carboxamide.However, these documents have no description that these compounds are a FAAH inhibitor.